The proposed research is directed at the long-term goal of gaining significant new knowledge of the functional contribution of brain monoaminergic systems to neurochemical mechanisms regulating neuronal activity during seizure discharge. The objectives include a characterization of the inhibitory role of monoaminergic involvement in seizure mechanisms to limit the spread of repetitive neuronal discharge and a determination of whether digitoxigenin has direct and/or indirect effects on these monoaminergic mechanisms. An assessment of brain monoaminergic involvement in convulsant thresholds and the contribution of specific brain monoamines to the effect of the digitoxigenin to lower convulsant thresholds will be determined in the adult rat. The convulsant threshold models (electroschock and pentylenetetrazol) will represent a range of spread of seizure discharge. This design will be extended to the young rat during postnatal brain maturation to determine the involvement of monoamines in the age-related development of seizure patterns, regulation of convulsant thresholds and effect of digitoxigenin on these parameters in order to relate the investigation to maturing inhibitory systems. The influence of repeated or continuous exposure of the postnatal maturing rat brain to digitoxigenin on monoaminergic mechanisms important to seizure discharge will provide information on the interaction of digitoxigenin with monoaminergic mechanisms which may be related to developing inhibitory systems. In the adult rat, research will be directed at the regional brain localization of digitoxigenin, an electrograhic characterization of the convulsant action of digitoxigenin and the effect of digitoxigenin on regional brain monoamine turnover rates, all related to the time course of digitoxigenin convulsions. Also, the effect of digitoxigenin on monoamine uptake and release using in vitro synaptosome systems prepared from specific brain regions will be determined. The results of the research, in a single animal species, should contribute significant new knowledge of the functional contribution of brain monoamines to neuronal regulation during seizure discharge.